The oral bioavailability of certain drugs can be improved by conversion to prodrugs. Certain prodrugs are derivatives of the parent drug in which a functional group is “masked” by a promoiety. Following administration to a patient the prodrug is metabolized to release the parent drug.
The 1-(acyloxy)-alkyl functionality is an example of a promoiety that has been used to functionalize amino containing drugs such as gabapentin, pregabalin, R-baclofen, and tranexamic acid. Gabapentin ([1-(aminomethyl)cyclohexyl]acetic acid) is an FDA approved drug that is marketed for the treatment of post herpetic neuralgia and epilepsy. 1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid is a 1-(acyloxy)-alkyl carbamate prodrug of gabapentin that has utility in the treatment of epilepsy (Gallop et al., WO 02100347), pain (Gallop et al., WO 02100347), particularly neuropathic pain or pain associated with irritable bowel syndrome, anxiety (Gallop et al., WO 02100347), particularly general anxiety disorder, alcohol dependency or ethanol withdrawal syndrome (Gallop et al., WO 02100347), restless legs syndrome (Barrett and Canafax, WO 2005027850), migraine prophylaxis (Barrett and Cundy, US 20080161393), fibromyalgia (Barrett and Cundy, US 20080161393), and hot flashes (Barrett and Gallop, WO 2004089289), particularly hot flashes associated with menopause. Pregabalin ((S)-3-(aminomethyl)-5-methyl-hexanoic acid) is an FDA approved drug that is marketed for the treatment of post herpetic neuralgia, fibromyalgia, and epilepsy. Pregabalin is not absorbed from the lower gastrointestinal tract and exhibits a short half life in vivo, and therefore frequent dosing is required to maintain therapeutic levels in the body. (3S)-{[1-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid, (3S)-{[1-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoic acid, and (3S)-{[1-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid are examples of 1-(acyloxy)-alkyl carbamate prodrugs of the GABA analog pregabalin, (3S)-aminomethyl-5-methyl-hexanoic acid, which exhibit high bioavailability as pregabalin when dosed either orally or directly into the colon of a mammal (Gallop et al., U.S. Pat. No. 6,972,341 and U.S. Pat. No. 7,186,855; and Yao et al., U.S. application Ser. Nos. 12/358,454 and 12/358,507 filed Jan. 23, 2009). The 1-(acyloxy)-alkyl promoiety has also been used to provide prodrugs of baclofen ((R)-4-amino-3-(4-chlorophenyl)butanoic acid). Gallop et al., U.S. Pat. No. 7,109,239 and U.S. Pat. No. 7,300,956 disclose 1-(acyloxy)-alkyl carbamate prodrugs of R-baclofen such as (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid. R-Baclofen is known to be useful for treating spasticity and gastro-esophageal reflux disease (van Herwaarden et al., Aliment. Pharmacol. Ther. 2002, 16(9), 1655-62; Ciccaglione and Marzio, Gut 2003, 52(4), 464-70; Andrews et al., U.S. Pat. No. 6,117,908; and Fara et al., WO 02096404); in promoting alcohol abstinence in alcoholics (Gessa et al., WO 0126638); in promoting smoking cessation (Gessa et al., WO 0108675); in reducing addiction liability of narcotic agents (Robson et al., U.S. Pat. No. 4,126,684); in the treatment of emesis (Bountra et al., U.S. Pat. No. 5,719,185); as an anti-tussive for the treatment of cough (Kreutner et al., U.S. Pat. No. 5,006,560); as well as for treating neuropathic and musculoskeletal pain (Benson et al., US 20090118365), movement disorders such as dystonia and hiccups; peripheral nerve disorders such as muscle stimulation disorders; spinal cord disorders such as spastic paraparesis; cranial nerve disorders such as glossopharyngeal neuralgia and trigeminal neuralgia; multiple sclerosis; and cerebral palsy.
The 1-(acyloxy)-alkyl promoiety has also been used to provide prodrugs of tranexamic acid (trans-4-(aminomethyl)-cyclohexanecarboxylic acid). For example, Zerangue et al., U.S. Pat. No. 7,351,740, disclose 1-(acyloxy)-alkyl carbamate prodrugs of tranexamic acid such as 4-({[(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)cyclohexanecarboxylic acid. Tranexamic acid is known to be useful in treating bleeding such as excessive menstrual bleeding (menorrhagia), bleeding associated with cardiac surgery, upper gastrointestinal hemorrhage, blood loss in patients with advanced cancer, bleeding that occurs during dental procedures in hemophiliacs and skin conditions such as wound healing, epidermal hyperplasia, skin roughening, unwanted skin pigmentation, and tumor metastasis (Zerangue et al., U.S. Pat. No. 7,351,740).
Methods of synthesizing 1-(acyloxy)-alkyl carbamate prodrugs are disclosed in Gallop et al., U.S. Pat. Nos. 6,818,787, 6,927,036, 6,972,341, 7,186,855, and 7,227,028; Raillard et al., U.S. Pat. No. 7,232,924; Gallop and Bhat, WO 2005/01001); and in Alexander, U.S. Pat. Nos. 4,760,057, 4,916,230, and 5,684,018.
Other methods of synthesizing 1-(acyloxy)alkyl carbamate prodrugs are more recently disclosed by Raillard et al., U.S. Provisional Application No. 61/087,056 filed Aug. 7, 2008.